FDA staff highlight Lykos data flaws for MDMA therapy

Scientists from the Food and Drug Administration (FDA) are expressing concerns regarding a new treatment for post-traumatic stress disorder (PTSD) that is awaiting approval. Lykos Therapeutics, an unconventional company, developed an ecstasy-based treatment that has undergone several clinical trials, including two late-stage, placebo-controlled studies. These studies form the primary evidence for the treatment's approval. In these trials, all participants received a psychological intervention, but those treated with midomafetamine, commonly known as MDMA, showed significant reductions in PTSD symptom severity.

Lykos believes that the positive outcomes from these trials justify the market release of their therapy. However, FDA staff remain skeptical. To resolve this, the FDA will convene an external panel of experts next week to evaluate the available evidence and vote on two critical questions: the therapy's effectiveness in treating PTSD and whether its benefits surpass the potential risks.

In documents prepared for the meeting, FDA staff raised concerns about the robustness of Lykos' data. They pointed out that interpreting the results is complicated by several factors, primarily the nature of the treatment. MDMA affects mood and cognition and can cause psychedelic experiences, such as altered perceptions of time and sensations. This makes it difficult to conduct trials without participants and researchers distinguishing between the drug and the placebo.

FDA staff highlighted that approximately 90% of the participants on Lykos' drug and 75% on the placebo could accurately guess their treatment assignment. This "functional unblinding" could skew trial results. Participants who believe they are taking the drug might report better outcomes, while those thinking they received a placebo might report worse ones.

Given the potential for unblinding, the FDA suggested that data from other sources might confirm whether the MDMA genuinely drove the results observed in Lykos' studies. The company did follow-up evaluations at least six months after the initial treatment, finding that PTSD symptoms had significantly reduced in patients given MDMA compared to those on a placebo. However, these results were not without flaws. The FDA noted that about 25% of participants dropped out between the main study and follow-up, with some undergoing therapeutic interventions during this period, complicating result interpretation.

Assessing the safety of Lykos' therapy also presents challenges. The safety database compiled by Lykos includes 426 participants exposed to MDMA in their trials and an additional 50 from studies by the National Institute on Drug Abuse. FDA staff acknowledged that this database might be adequate for a severe condition like PTSD. However, they criticized Lykos for not collecting enough data on the potential cardiovascular and liver health risks associated with the drug.

Lykos was also advised to document any adverse events linked to MDMA abuse, but the company failed to do so for effects deemed positive, favorable, or neutral, such as euphoria or elevated mood. This lack of information restricts the assessment of the abuse potential of the drug, according to the FDA. If Lykos' therapy is approved, the agency would likely require additional post-marketing safety data, including liver function tests.

Despite these concerns, FDA staff acknowledged the positive outcomes from Lykos' studies for a condition that is both widespread and challenging to treat. Estimates suggest that around 5% of people in the U.S. suffer from PTSD each year. While SSRI drugs can be effective, their full effects often take months to manifest, and response rates rarely exceed 60%.

Although the application has several complex review issues, it includes two positive studies where participants in the MDMA group showed statistically significant and clinically meaningful improvements in their PTSD symptoms, which appeared durable for several months. Lykos argued that the potential risks of their therapy could be managed through physician education, product labeling, and a Risk Evaluation and Mitigation Strategies (REMS) program.

If approved, Lykos' therapy would offer PTSD patients a novel treatment approach that involves a psychological intervention combined with acute pharmacological benefits.